This invention relates to devices useful for the delivery of a beneficial agent to an environment of use.
In an osmotic device water is imbibed into the device across a semi-permeable membrane due to a lower concentration of water in the device core than in the environment of use. This creates a positive hydrostatic pressure in the device core resulting in release of the beneficial agent contained in the core. Most osmotic delivery systems provide sustained delivery of a beneficial agent (e.g., Baker, R. W., 1987, Controlled Release of Biologically Active Agents John Wiley & Sons pp 132-155; and Smith, K. L. and Herbig, S. M., 1992 "Controlled Release" in Membrane Handbook Ho, W. S. W., and Sirkar, K. K., eds., Van Nostrand Reinhold, pp 915-935).
Osmotic devices have also been developed that release the beneficial agent as a bolus (osmotic bursting systems) (e.g. U.S. Pat. Nos. 3,247,066; 3,952,741; 4,016,880; and 4,177,256). The release of the beneficial agents is initiated once the delivery device is immersed in aqueous solutions.
In an alternative method of delivery of beneficial agents, devices have been developed that dissolve at a specific pH in order to release the agent. Release of the beneficial agent from these formulations is caused by the dissolution of the enteric coating and the subsequent dissolution and/or diffusion of the core components into a receptor solution. Materials that dissolve due to specific pH are commonly used in the pharmaceutical industry as coatings for tablets, particles and capsules. The use of pH-sensitive materials as coatings is described in most reference books describing pharmaceutical formulations.
Typically pH-sensitive materials have been used as coatings to protect labile beneficial agents, or to encapsulate irritating beneficial agents during transit through the stomach, and then release the beneficial agent shortly after entering the small intestine. These coatings have been modified to achieve longer time lags prior to release so that the beneficial agent can be released in the lower end of the small intestine or in the colon. However, these coatings function similarly as common enteric coatings. pH-sensitive coatings that achieve delivery in the colon have been described in patents such as U.S. Pat. No. 4,910,021 and WO 9001329. U.S. Pat. No. 4,910,021 describes using pH-sensitive material to coat a capsule and WO 9001329 describes pH-sensitive coatings on beads containing acid. The acid in the bead core prolongs dissolution of the pH-sensitive coating.
The use of pH-sensitive materials alone to achieve site-specific delivery is difficult because of the problem of leaking beneficial agent prior to the release site or desired delivery time. Typically 10% to 30% of the total beneficial agent is released prematurely. In addition, it is difficult to achieve long time lags before release of the active ingredient after exposure to high pH (because of rapid dissolution or degradation of the pH-sensitive materials).
There are also hybrid systems which combine pH-sensitive materials and osmotic delivery systems. These devices provide for delayed initiation of sustained-release of the beneficial agent. In one device a pH-sensitive matrix or coating dissolves releasing osmotic devices that provide sustained release of the beneficial agent (U.S. Pat. Nos. 4,578,075; 4,681,583; and 4,851,231). A second device consists of a semipermeable coating made of a polymer blend of insoluble and pH-sensitive material. As the pH increases, the permeability of the coating increases, increasing the rate of release of beneficial agent (U.S. Pat. Nos. 4,096,238; 4,503,030; 4,522,625; and 4,587,117).
Another system consists of a "push-pull" osmotic device with a pH-sensitive barrier inside of the semipermeable coating. The pH-sensitive barrier delays sustained osmotic delivery until it is dissolved in high pH solution (U.S. Pat. No. 4,904,474). In yet another system the device has a trilaminate coating consisting of a semipermeable coating, a fatty acid salt or osmotic solute coating, and an outer enteric coating. Due to dissolution of the outer enteric layer, sustained osmotic delivery of the beneficial agent is initiated after exposure to high pH solutions (U.S. Pat. Nos. 4,627,851; 4,693,895; and 4,705,515).
The four above-described osmotic devices with pH-sensitive coatings provide for sustained release of beneficial agent through a drug delivery port by osmotic pumping. The key to the operation of these osmotic systems is an increase in coating permeability as the pH-sensitive coatings dissolve. The release kinetics are affected by the pH-sensitive material either by controlling the time and/or location of delivery or the rate of delivery.
Although the above devices make a significant advance in the field of osmotic delivery devices there is a continuing search for alternative osmotic delivery devices.